The role of the pineal gland and its hormone, melatonin, has been difficult to define in humans, because the circulating levels of melatonin have been too low to measure. In collaboration with Dr. S. Markey of the LCS, we have developed a highly sensitive and specific gas chromatographic-mass spectrometric (GC-MS) assay which required less than 1 ml of human plasma, CSF, or urine. We are currently investigating: (1) the circadian pattern of secretion of melatonin in normal individuals and its lateration in a variety of disease states (such as depression, mania, and blindness); (2) sensitivity of patients and normal subjects to light suppression of nocturnal melatonin secretion; (3) the effect of drugs on light suppression of melatonin secretion. We have found that manic-depressive patients are abnormally sensitive to light; that clorgyline, a monoamine oxidase type A inhibitor that is used to treated manic-depressives desensitizes hamsters melatonin suppression by light; and that blind subjects have markedly abnormal timing of the circadian rhythm in melatonin secretion, in some cases because the rhythm is no longer entrained to the day-night cycle, but is free-running according to its own 25-hour rhythm. This last result underlines the importance of light and sensitivity to light in the normal homeostasis of circadian rhythm phases (phases that are disordered in manic-depressive illness).